Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality worldwide. A major risk factor for HCC, the most common type of primary liver cancer, is cirrhosis, frequently caused by chronic viral hepatitis, alcohol abuse, and nonalcoholic fatty liver disease. Although treatment of HCC has greatly improved over the last decades, most HCC patients diagnosed at advanced stages are ineligible for curative ablative therapies such as liver resection or transplantation. The use of the multikinase inhibitor sorafenib in patients with advanced HCC suggests that targeted therapies could be beneficial in this cancer; however, this regimen only extends life expectancy from 8 to 11 months, highlighting the urgent need for new therapeutic approaches.
Recent developments in gene-expression profiling technologies have enabled the molecular classification of HCCs into defined subclasses, creating a solid foundation on which to build more informative clinical trials. Furthermore, exhaustive genomic studies have identified MYC genomic amplifications, β-catenin mutations, and tumor suppressor TP53 inactivation as frequent events in HCC. However, unlike other tumor types, which present genetic drivers that can be therapeutically exploited, such as EGFR mutations in lung cancer and BRAF mutations in melanoma, HCC is genetically heterogeneous and lacks clearly targetable genetic drivers. Thus, it seems likely that more insights into the function of currently “undruggable” genetic lesions will be necessary to develop rational therapies for this disease.